Chi Zhang

Trabecular meshwork (TM) tissue is highly specialized, and its structural integrity is crucial for maintaining homeostatic intraocular pressure (IOP). The administration of glucocorticoids, such as dexamethasone (DEX), can perturb the TM structure and significantly increase IOP in susceptible individuals, resulting in ocular diseases such as steroid-induced glaucoma, a form of open-angle glaucoma. Although the exact mechanism involved in steroid-induced glaucoma remains elusive, increasing evidence suggests that DEX may act through various signaling cascades in TM cells. Despite uncertainty surrounding the specific process by which steroid-induced glaucoma occurs, there is growing evidence to indicate that DEX can impact multiple signaling pathways within TM cells. In this study, we examined the impact of DEX treatment on the Wnt signaling pathway in TM cells, given that Wnt signaling has been reported to play a crucial role in regulating extracellular matrix (ECM) levels in the TM. To further elucidate the role of Wnt signaling in the glaucomatous phenotype, we examined mRNA expression patterns between Wnt signaling markers AXIN2 and sFRP1 and DEX-mediated induction of myocilin (MYOC) mRNA and protein levels over 10 days in DEX-treated primary TM cells. We observed a sequential pattern of peak expression between AXIN2, sFRP1, and MYOC. Based on the study, we propose that sFRP1 upregulation could be a result of a negative feedback mechanism generated by stressed TM cells to suppress abnormal Wnt signaling activities.

Glaucoma is the leading cause of irreversible blindness worldwide, with elevated intraocular pressure (IOP) as the only known modifiable risk factor. Trabecular meshwork (TM)-inducible myocilin (the MYOC gene) was the first to be identified and linked to juvenile and primary open-angle glaucoma. It has been suggested that mutations in the MYOC gene and the aggregation of mutant myocilin in the endoplasmic reticulum (ER) of TM may cause ER stress, resulting in a reduced outflow of aqueous humor and an increase in IOP. We selected 20 MYOC mutations with experimentally determined melting temperatures of mutated myocilin proteins. We included 40 published studies with at least one glaucoma patient with one of these 20 MYOC mutations and information on age at glaucoma diagnosis. Based on data from 458 patients, we found that a statistically significant but weak correlation was present between age and melting temperature based on various assumptions for age. We therefore conclude that genetic analysis of MYOC mutations alone cannot be used to accurately predict age at glaucoma diagnosis. However, it might be an important prognostic factor combined with other clinical factors for critical and early detection of glaucoma.